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Editorial |

Severe Sarcoidosis Phenotypes: An Occupational Hazard? FREE TO VIEW

Elliott D. Crouser, MD; Emily N. Amin, MD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: E. D. C. is a consultant for Beckman Coulter, Inc. and clinical trial investigator for Bristol-Myers Squibb. None declared (E. N. A.).

Davis Heart & Lung Institute, The Ohio State University Wexner Medical Center, Columbus, OH

CORRESPONDENCE TO: Elliott D. Crouser, MD, Room 201, Davis Heart & Lung Institute, 473 W 12th Ave, The Ohio State University Wexner Medical Center, Columbus, OH 43210


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(2):263-265. doi:10.1016/j.chest.2016.02.663
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Published online

The cause of sarcoidosis remains elusive; however, most experts agree upon several “essential ingredients.” Strong evidence implicates genetic factors predisposing certain individuals to the development of sarcoidosis. The evolutionary factors driving these genetic characteristics are unclear, but a reasonable case could be made for the sarcoidosis genotype being protective against common human infections, including MycobacteriumTB. Many sarcoidosis patients are hyperresponsive to immunogenic TB antigens in the absence of active or latent TB infection. That said, the immune response is not TB-specific, because immune cells derived from patients with sarcoidosis produce abnormally high levels of Th1 cytokines under conditions modeling the immune response to antigens present in an array of bacteria and fungi. Thus, it is not surprising that numerous organisms (and molecules) are incriminated in the pathogenesis of sarcoidosis.

FOR RELATED ARTICLE SEE PAGE 289

Environmental antigens are considered essential for pathological granuloma formation in exposed host tissues, including the lungs, skin, and lymphatics. The nature of the environmental exposure, including the intensity, duration, and molecular composition, are variables that likely dictate the development and progression of sarcoidosis. More often than not, a single inciting exposure is not identified, implicating longitudinal antigen exposures, such as commonly occurs in the workplace. In this regard, A Case-Control Etiologic Sarcoidosis Study (ACCESS) surveyed 736 US sarcoidosis patients within 6 months of establishing the diagnosis to ascertain the etiology of sarcoidosis by considering occupational, environmental, and lifestyle factors showing positive associations with exposures to insecticides, agricultural employment, and moldy environments. Notably, as was previously observed in a European study, ACCESS showed a strong negative association with smoking cigarettes. Though inconclusive in terms of identifying a specific sarcoidosis etiology, ACCESS and other related studies provide convincing evidence linking occupational and lifestyle-related exposures to the pathogenesis of sarcoidosis.

Little is known about environmental factors specifically influencing sarcoidosis disease progression, particularly factors promoting severe sarcoidosis phenotypes leading to premature death. In the current issue of CHEST, Liu et al took advantage of a large dataset compiled by the US National Center for Health Statistics from 1988 to 1999 that provided the cause of death per physician coding using the 9th and 10th Revision of the International Classification of Diseases. The study population exceeded 7 million decedents > 14 years of age from 25 US states with concurrent occupational histories, from which the mortality OR (MOR) for a given occupational exposure was calculated among decedents with sarcoidosis as a primary or secondary cause of death. The incidence of death attendant to a particular occupational exposure was indeterminable because the total number of individuals holding a given occupation in these 25 states at any given time was unknown, and many subjects had more than one occupation. Beyond the role of occupation, the study further considered the influences of sex and race on sarcoidosis mortality.

The results are compelling, with a mixture of expected and unanticipated findings. In keeping with the presupposition that occupational exposures influences disease phenotypes, sarcoidosis-related mortality was generally higher among decedents who had any type of occupational exposure. For many occupational exposures, significant excess sarcoidosis-related mortality was strongly influenced by female sex and black race, factors also associated with higher disease prevalence. This finding is in keeping with recent observations from the Nurses’ Health Study II, a large, prospective study of US female nurses, wherein the risk-adjusted mortality of black women with sarcoidosis was nearly 2-fold greater than the matching control group of black women who did not have sarcoidosis. Thus, all things being equal, including work exposures, black women are distinguished by their increased susceptibility to sarcoidosis and higher associated mortality.

Work exposures commonly cause antigen-mediated Th1 immune responses leading to lung disease; the classic example being hypersensitivity pneumonitis, such as occurs in the setting of metal working, agriculture, and lumber occupations. Likewise, the ACCESS trial identified “building materials” and “industrial organic dusts” (including agricultural), and, to a lesser degree “education” as occupations that were positively associated with the diagnosis of sarcoidosis. Thus, it is not surprising that the occupations characterized as “metal” (eg, welding, machine-operators) and “teach” (teachers) had higher sarcoidosis MOR among sarcoidosis patients. However, it is interesting that neither “agri” (agricultural) nor “organic” (eg, organic dusts) occupations influenced sarcoidosis MOR. “Silica” (eg, stone, glass or mine workers) was the only occupation associated with a lower MOR, which is mechanistically plausible given that silica favors a Th2 immune response. Thus, the study by Liu et al shows for the first time that certain exposures, some linked to the etiology of sarcoidosis or hypersensitivity pneumonitis, may promote more severe sarcoidosis phenotypes and associated mortality. This study also adds to the evidence indicating that a variety of exposures, and presumably different antigens, influence the granulomatous response in sarcoidosis.

Unexpectedly, occupations categorized as “health,” “teach,” “bank,” and “admin” were associated with significantly higher MOR; whereas “fire” (firefighting) was not. Women with “admin” and “bank” employment histories had the highest MOR compared with men. The explanation for this observation may primarily relate to genetics; however, it is interesting to speculate that associated lifestyle differences, such as the routine use of hairspray or cosmetics, could play a role, such as was previously reported.,, On the other hand, the finding of no significant MOR increase in the “fire” category is somewhat unexpected given the well-documented cases of new-onset pulmonary sarcoidosis following a large, acute exposure to smoke, dust, and fumes during the September 11, 2011, catastrophe in New York City; especially among black firefighters. It is interesting to speculate that the form of sarcoidosis that develops in response to a single, large exposure to antigen is phenotypically distinct from sarcoidosis that develops after multiple, less-intense exposures. Indeed, one of the previously mentioned cases of possible hairspray-associated pulmonary sarcoidosis completely resolved after the patient was removed from her occupational environment. Thus, prolonged or repeated occupational exposures may be required for the development of more severe sarcoidosis phenotypes, such as those leading to premature death. Unfortunately, the duration or intensity of the occupational exposures was not apparent from the information provided in the death certificates used for the study by Liu et al.

As noted by the authors, the study population comprises a cross-section of the United States derived from 25 states. The influence of this selection bias is unclear, but it is likely that exclusion of 50% of the states would skew the data toward certain occupations and racial groups. Nonetheless, the study is impactful in that it provides the largest available US sample from which the occupational impact on sarcoidosis mortality has been determined.

The influence of smoking on sarcoidosis disease severity and mortality are currently unknown. Whereas smoking is shown to reduce disease risk, it also increases the activity of alveolar macrophages and associated biomarkers of sarcoidosis activity. Does this increase in macrophage activity translate to a more severe sarcoidosis phenotype? This question remains unanswered as data regarding smoking status were unavailable from the death certificates used for this study.

As indicated by well-documented temporal and regional clustering of new sarcoidosis cases,, environmental factors play a significant role in the pathogenesis of sarcoidosis. The study by Liu et al further incriminates occupational factors that influence severe sarcoidosis disease phenotypes, with life-altering implications. More studies of this type are indicated to help identify occupational exposures that are to be avoided in patients with sarcoidosis.

Supplementary Data

Fingerlin T.E. .Hamzeh N. .Maier L.A. . Genetics of sarcoidosis. Clin Chest Med. 2015;36:569-584 [PubMed]journal. [CrossRef] [PubMed]
 
Song Z. .Marzilli L. .Greenlee B.M. .et al Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med. 2005;201:755-767 [PubMed]journal. [CrossRef] [PubMed]
 
Wilken M. .Grunewald J. .Eklund A. .Wahlstrom J. . Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis. J Clin Immunol. 2009;29:78-89 [PubMed]journal. [CrossRef] [PubMed]
 
Valeyre D. .Prasse A. .Nunes H. .Uzunhan Y. .Brillet P.Y. .Muller-Quernheim J.M. . Sarcoidosis. Lancet. 2014;383:1155-1167 [PubMed]journal. [CrossRef] [PubMed]
 
Newman L.S. .Rose C.S. .Bresnitz E.A. .et al ACCESS Research Group. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170:1324-1330 [PubMed]journal. [CrossRef] [PubMed]
 
Valeyre D. .Soler P. .Clerici C. .Pre J. .Battesti J.P. .Georges R. .Hance A.J. . Smoking and pulmonary sarcoidosis: effect of cigarette smoking on prevalence, clinical manifestations, alveolitis, and evolution of the disease. Thorax. 1988;43:516-524 [PubMed]journal. [CrossRef] [PubMed]
 
Liu H. .Patel D. .Welch A.M. .et al Association between occupational exposures and sarcoidosis: an analysis from death certificates in the United States, 1988-1999. Chest. 2016;150:289-298 [PubMed]journal
 
Baughman R.P. .Teirsten A.S. .Judson M.A. . Case Control Etiologic Study of Sarcoidosis (ACCESS) research groupet al Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164:1885-1889 [PubMed]journal. [CrossRef] [PubMed]
 
Dumas O. .Abramovitz L. .Wiley A.S. .Cozier Y.C. .Carmargo C.A. Jr.. Epidemiology of sarcoidosis in a prospective cohort study of U.S. women. Ann Am Thorac Soc. 2016;13:67-71 [PubMed]journal. [CrossRef] [PubMed]
 
Tillie-LeBlond I. .Grenouillet F. .Reboux G. .et al Hypersensitivity pneumonitis and metalworking fluids contaminated by mycobacteria. Eur Respir J. 2011;37:640-647 [PubMed]journal. [CrossRef] [PubMed]
 
Nordgren T.M. .Bailey K.L. . Pulmonary health effects of agriculture. Curr Opin Pulm Med. 2016;22:144-149 [PubMed]journal. [CrossRef] [PubMed]
 
Faerden K. .Lund M.B. .Aalokken T. .et al Hypersensitivity pneumonitis in a cluster of sawmill workers: a 10-year follow-up of exposure, symptoms, and lung function. Int J Occup Environ Health. 2014;20:167-173 [PubMed]journal. [CrossRef] [PubMed]
 
Barnard J. .Rose C. .Newman L. .et al ACCESS Research Group. Job and industry classifications associated with sarcoidosis in A Case-Control Etiologic Study of Sarcoidosis (ACCESS). J Occup Environ Med. 2005;47:226-234 [PubMed]journal. [CrossRef] [PubMed]
 
Kuroda E. .Ishii K.J. .Uematsu S. .et al Silica crystals and aluminum salts regulate the production of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms. Immunity. 2011;43:514-526 [PubMed]journal
 
Bergmann M. .Flance I.J. .Cruz P.T. .et al Thesaurosis due to inhalation of hair spray: report of twelve cases, including three autopsies. New Engl J Med. 1962;266:750-755 [PubMed]journal. [CrossRef] [PubMed]
 
Herrero E.U. .Feigelson H.H. .Becker A. . Sarcoidosis in a beautician. Am Rev Respir Dis. 1965;92:280-283 [PubMed]journal. [PubMed]
 
Marcoval J. .Mana J. .Penin R.M. .Figueras I. .Labori M. .Llatjos R. . Sarcoidosis associated with cosmetic fillers. Clin Exp Dermatol. 2014;39:397-399 [PubMed]journal. [CrossRef] [PubMed]
 
Crowley L.E. .Herbert R. .Moline J.M. .et al “Sarcoid like” granulomatous pulmonary disease in World Trade Center disaster responders. Am J Ind Med. 2011;54:175-184 [PubMed]journal. [CrossRef] [PubMed]
 
Hills S.E. .Parkes S.A. .Baker S.B. . Epidemiology of sarcoidosis in the Isle of Man-2: evidence for space-time clustering. Thorax. 1987;42:427-430 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Fingerlin T.E. .Hamzeh N. .Maier L.A. . Genetics of sarcoidosis. Clin Chest Med. 2015;36:569-584 [PubMed]journal. [CrossRef] [PubMed]
 
Song Z. .Marzilli L. .Greenlee B.M. .et al Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med. 2005;201:755-767 [PubMed]journal. [CrossRef] [PubMed]
 
Wilken M. .Grunewald J. .Eklund A. .Wahlstrom J. . Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis. J Clin Immunol. 2009;29:78-89 [PubMed]journal. [CrossRef] [PubMed]
 
Valeyre D. .Prasse A. .Nunes H. .Uzunhan Y. .Brillet P.Y. .Muller-Quernheim J.M. . Sarcoidosis. Lancet. 2014;383:1155-1167 [PubMed]journal. [CrossRef] [PubMed]
 
Newman L.S. .Rose C.S. .Bresnitz E.A. .et al ACCESS Research Group. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170:1324-1330 [PubMed]journal. [CrossRef] [PubMed]
 
Valeyre D. .Soler P. .Clerici C. .Pre J. .Battesti J.P. .Georges R. .Hance A.J. . Smoking and pulmonary sarcoidosis: effect of cigarette smoking on prevalence, clinical manifestations, alveolitis, and evolution of the disease. Thorax. 1988;43:516-524 [PubMed]journal. [CrossRef] [PubMed]
 
Liu H. .Patel D. .Welch A.M. .et al Association between occupational exposures and sarcoidosis: an analysis from death certificates in the United States, 1988-1999. Chest. 2016;150:289-298 [PubMed]journal
 
Baughman R.P. .Teirsten A.S. .Judson M.A. . Case Control Etiologic Study of Sarcoidosis (ACCESS) research groupet al Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164:1885-1889 [PubMed]journal. [CrossRef] [PubMed]
 
Dumas O. .Abramovitz L. .Wiley A.S. .Cozier Y.C. .Carmargo C.A. Jr.. Epidemiology of sarcoidosis in a prospective cohort study of U.S. women. Ann Am Thorac Soc. 2016;13:67-71 [PubMed]journal. [CrossRef] [PubMed]
 
Tillie-LeBlond I. .Grenouillet F. .Reboux G. .et al Hypersensitivity pneumonitis and metalworking fluids contaminated by mycobacteria. Eur Respir J. 2011;37:640-647 [PubMed]journal. [CrossRef] [PubMed]
 
Nordgren T.M. .Bailey K.L. . Pulmonary health effects of agriculture. Curr Opin Pulm Med. 2016;22:144-149 [PubMed]journal. [CrossRef] [PubMed]
 
Faerden K. .Lund M.B. .Aalokken T. .et al Hypersensitivity pneumonitis in a cluster of sawmill workers: a 10-year follow-up of exposure, symptoms, and lung function. Int J Occup Environ Health. 2014;20:167-173 [PubMed]journal. [CrossRef] [PubMed]
 
Barnard J. .Rose C. .Newman L. .et al ACCESS Research Group. Job and industry classifications associated with sarcoidosis in A Case-Control Etiologic Study of Sarcoidosis (ACCESS). J Occup Environ Med. 2005;47:226-234 [PubMed]journal. [CrossRef] [PubMed]
 
Kuroda E. .Ishii K.J. .Uematsu S. .et al Silica crystals and aluminum salts regulate the production of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms. Immunity. 2011;43:514-526 [PubMed]journal
 
Bergmann M. .Flance I.J. .Cruz P.T. .et al Thesaurosis due to inhalation of hair spray: report of twelve cases, including three autopsies. New Engl J Med. 1962;266:750-755 [PubMed]journal. [CrossRef] [PubMed]
 
Herrero E.U. .Feigelson H.H. .Becker A. . Sarcoidosis in a beautician. Am Rev Respir Dis. 1965;92:280-283 [PubMed]journal. [PubMed]
 
Marcoval J. .Mana J. .Penin R.M. .Figueras I. .Labori M. .Llatjos R. . Sarcoidosis associated with cosmetic fillers. Clin Exp Dermatol. 2014;39:397-399 [PubMed]journal. [CrossRef] [PubMed]
 
Crowley L.E. .Herbert R. .Moline J.M. .et al “Sarcoid like” granulomatous pulmonary disease in World Trade Center disaster responders. Am J Ind Med. 2011;54:175-184 [PubMed]journal. [CrossRef] [PubMed]
 
Hills S.E. .Parkes S.A. .Baker S.B. . Epidemiology of sarcoidosis in the Isle of Man-2: evidence for space-time clustering. Thorax. 1987;42:427-430 [PubMed]journal. [CrossRef] [PubMed]
 
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